The present invention relates to an agent for inhibition of cytokine production and an agent for inhibition of cell adhesion.
A number of cytokines were discovered as protein factors which inhibit the expression of human physiological activities such as immune response, inflammation, hematopoiesis and the like, and their structures and functions have gradually been made clear. As a result, it is being clarified that the cytokines affect not only human immunological system but also various other human physiological activities and further have a close connection with the development, differentiation, homeostatis and diseases of human body.
Many cytokines such as TNF-xcex1, IL-1xcex2, IL-6, IFN-xcex3 and the like are identified. It is known that they also have various pharmacological activities.
Of the above cytokines, TNF-xcex1 (Tumor necrosis factor-xcex1) was discovered as an antineoplastic cytokine and was expected to be used as an anticancer agent. However, TNF-xcex1 was later found to be the same substance as cachectin (a cachexia inducer) and is reported to have, for example, a stimulating activity for production of IL-1 and other cytokines, an activity of proliferation of fibroblast, an endotoxin shock-inducing activity, an activity for increasing ICAM-1, ICAM-2 (intercellular adhesion molecules), ELAM (endothelial leukocyte adhesion molecule-1), etc. (these molecules are proteins for adhering leukocytes to endothelial cells) to accelerate the adhesion of leukocytes to endothelial cells, and an arthritis-causing activity such as bone resorption, cartilage destruction or the like [Beutler, B., et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989); Akatu, K. and Suda, T., Medical Practice, 8 (9) 1393-1396 (1991)].
It is also reported that the concentration of TNF in blood or neurolymph increases in infectious diseases by bacteria or parasites [Mitsuyama, M., Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), 159 (8) 467-470 (1991); Nakao, M., Journal of Clinical and Experimental Medicine (IGAKU NOA-YUMI), 159 (8) 471-474 (1991)].
It is also reported that the activity of TNF is found in synovial fluid or serum, in chronic rheumatoid arthritis and that the activity is a TNF-xcex1 activity [Saxne, T., et al., Arthritis Rheum., 31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 (1991); Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990); Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); Brennan, F. M., et al., Bri. J. Rheum., 31, 293-298 (1992)].
It is also reported that the concentration of TNF is high in the sputa of patients of ARDS (acute respiratory distress syndrome) which is a serious respiratory disease [Millar, A. B., et al., Nature, 324, 73 (1986)] and that TNF is associated with viral fulminant hepatitis [Muto, Y., et al., Lancet, ii, 72-74 (1986)].
It is also reported that the concentration of TNF-xcex1 in blood is high in myocardial ischemia such as acute myocardial infarction [Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)]. It is suggested that TNF-xcex1 is associated with such a disease [Lefer, A. M., et al., Science, 249, 61-64 (1990)]. It has recently been reported that TNF-xcex1 suppresses myocardial contractility [Finkel, M. S., et al., Science, 257, 387-389 (1992); Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)].
Currently, no satisfactory chemotherapy is developed yet for the above-mentioned various diseases such as chronic rheumatoid arthritis, endotoxin shock, ARDS and the like. To these diseases are merely applied, in a symptomatic treatment, steroidal agents, anti-inflammatory agents, agents for inhibition of platelet agglutination, antibiotics, etc. As it was suggested as mentioned above that there is a close connection between the above diseases and the rise in concentration or activity of TNF-xcex1, it has recently been tried to apply TNF-xcex1 antibody or the like to the diseases; however, such an approach has given no satisfactory result, either. Therefore, it is desired in the art to develop a drug for treatment of the above diseases, which can suppress the excessive production of, in particular, TNF-xcex1, according to a novel mechanism.
B cells are activated by antigen, proliferated and differentiated into antibody-producing cells. IL-6 is known to be a cytokine participating in this differentiation.
It is clear that IL-6 not only plays an important role in antibody production of B cells, but also induces the proliferation and differentiation of T cells. It is also clear that IL-6 acts on liver cells to induce the synthesis of proteins in acute phase, acts on hemopoietic cells to promote the formation of pluripotential colonies, and is an important factor in biophylactic systems such as immune system, hemopoietic system, nerve system, liver and the like.
As the diseases with which IL-6 is associated, there are mentioned a series of autoimmune diseases such as hyper-xcex3-globulinemia, chronic rheumatoid arthritis, systemic lupus erythematosus (SLE) and the like; monoclonal B cell abnormal disease (e.g. myeloma); polyclonal B cell abnormal disease; atrial myxoma; Castleman syndrome; primary glomerulonephritis; mesangial proliferative nephritis; cancerous cachexia; Lennander""s lymphoma; psoriasis; Kaposi""s sarcoma appearing in AIDS; postmenopausal osteoporosis; and so forth.
IL-1xcex2 is known to have various physiological activities. Specific examples of these activities are inhibition of tumor cell, increase of cytokine production from activated T cells, proliferation of fibroblast, synoviocyte and vessel endothelium, catabolism and thermacogenesis of cell, differentiation of activated B cell, increase of NK activity, adhesion of neutrophils, anti-inflammation, inhibition of radiation disorder, etc.
When IL-1xcex2 is produced at an increased rate and becomes excessive, IL-1xcex2 is thought to give rise to various diseases such as chronic rheumatoid arthritis, chronic inflammatory diseases and the like.
IFN is known to have various physiological activities and is actually detected in tissues and blood during many diseases. The diseases whose onset is considered to have a close connection with IFN, include viral infectious diseases, infectious diseases by microorganisms other than viruses, chronic rheumatoid arthritis, collagen diseases (e.g. SLE), I-type allergy, uveitis, Behcet""s disease, sarcoidosis, arteriosclerosis, diabetes, fulminant hepatitis, malignant tumor, Kawasaki disease, wounds of skin or mucosa, etc. [Journal of Clinical and Experimental Medicine (IGAKU NO AYUMI), 174 (14), p. 1077, 1995].
Neutrophils express a bactericidal action to the enemy incoming into human body, by migration, phagocytosis, production of reactive oxygen and release of lysosomal enzymes. However, neutrophils are known to adhere to vascular endothelial cells and further infiltrate into tissues during the ischemia or reperfusion, or acute inflammation of various tissues, leading to tissue disorder.
As stated above, various cytokines are known to cause various diseases when the cytokines become excessive owing to, for example, the abnormally high production thereof. Therefore, it is desired to ameliorate the abnormal state of cytokine to prevent or treat various diseases.
It is also desired to develop an agent for inhibiting the tissue disorder caused by adhesion of neutrophils to vascular endothelial cells.
Some of the thiazole derivatives represented by the following general formula (1): 
[wherein R1 is a phenyl group which may have a lower alkoxy group(s) as a substituent(s) on the phenyl ring; and R2 is a group represented by the following general formula: 
[wherein R3""s, which may be the same or different, are each a carboxyl group, a lower alkoxy group, a lower alkyl group, a lower alkenyl group, a group represented by xe2x80x94(A)lxe2x80x94NR4R5 (A is a lower alkylene group; R4 and R5, which may be the same or different, are each a hydrogen atom or a lower alkyl group; and l is 0 or 1), a hydroxyl group-substituted lower alkyl group, a lower alkoxy group-substituted lower alkoxy group, a lower alkoxy group-substituted lower alkoxycarbonyl group or a carboxyl group-substituted lower alkoxy group; and m is an integer of 1-3], or a heterocyclic ring residue having 1-2 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which heterocyclic ring residue may have, as a substituent(s) on the heterocyclic ring, 1-3 groups selected from the group consisting of carboxyl group and lower alkoxy group) and salts thereof, are known in, for example, JP-A-5-51318 and JP-A-6-65222. These thiazole derivatives and salts thereof are also well-known to be useful as a reactive oxygen inhibitor.
The object of the present invention is to provide an agent for inhibiting the abnormally high production of cytokines or adhesion of neutrophils to vascular endothelial cells, which satisfies the requirements of the art, i.e. an agent for inhibiting cytokine production or an agent for inhibiting cell adhesion.
The present inventor made a further study on the pharmacological actions of the thiazole derivatives represented by the above general formula (1) and salts thereof. As a result, the present inventor found out that these thiazole derivatives and salts thereof can act as an agent for inhibiting cytokine production or an agent for inhibiting cell adhesion, both satisfying the above object of the present invention. The present invention has been completed based on the finding.
According to the present invention, there is provided an agent for inhibiting cytokine production, comprising, as the active ingredient, at least one compound selected from the group consisting of thiazole derivatives represented by the above general formula (1) and salts thereof.
According to the present invention, there is also provided an agent for inhibiting cell adhesion, comprising, as the active ingredient, at least one compound selected from the group consisting of thiazole derivatives represented by the above general formula (1) and salts thereof.
According to the present invention, there is also provided an agent for inhibiting TNF-xcex1 production, comprising, as the active ingredient, at least one compound selected from the group consisting of thiazole derivatives represented by the above general formula (1) and salts thereof.
Of the thiazole derivatives represented by the general formula (1), preferred is 6-[2-(3,4-diethoxyphenyl)thiazole-4-yl]pyridine-2-carboxylic acid.
As mentioned previously, some of the thiazole derivatives of the general formula (1) and salts thereof and production processes thereof are described in JP-A-5-51318-and JP-A-6-65222, and these thiazole derivatives are known to be useful as an agent for inhibiting reactive oxygen. Meanwhile, the inhibition of cytokine production or cell adhesion according to the present invention has no connection with the above-mentioned inhibition of reactive oxygen by thiazole derivatives and is unpredictable from the inhibition of reactive oxygen.
The agent for inhibiting cytokine production or cell adhesion according to the present invention is useful for various diseases associated with the abnormally high production of cytokines, particularly TNF-xcex1, IL-1xcex2, IL-6 and IFN-xcex3, or with increased adhesion. The present agent can be suitably used as a preventive or therapeutic agent particularly for chronic rheumatoid arthritis; endotoxin shock; ARDS caused by aspiration of gastric contents, toxic gas, sepsis, etc.; burn; asthma; myocardial infarction in myocardial ischemia; viral myocarditis in acute phase; chronic heart failure (e.g. idiopathetic dilated cardiomyopathy); etc. The present agent can also be suitably used as a preventive or therapeutic agent for ischemia-reperfusion injury caused at the time of coronary arterial bypass graft (CABG) or the use of artificial heart lung apparatus; shift from systemic inflammatory response syndrome (SIRS) toward organ failure (e.g. severe acute pancreatitis, disseminated intravasocular coagulation (DIC)); multiple organ failure caused by hepatic insufficiency after hepatectomy such as resection of hepatic cancer, or acute pancreatitis; severe acute pancreatitis; inflammatory bowel diseases such as ulcerative colitis, Crohn disease and the like; a series of autoimmune diseases such as hyper-xcex3-globulinemia, chronic rheumatoid arthritis, systemic lupus erythematosus (SLE), multiple sclerosis and the like; metastasis of cancer; rejection in transplantation; monoclonal B cell abnormal disease (e.g. myeloma); polyclonal B cell abnormal disease; atrial myxoma; Castleman syndrome; primary glomerulonephritis; mesangial proliferative glomerulonephritis; cancerous cachexia; Lennander""s lymphoma; psoriasis; atopic dermatitis; Kaposi""s sarcoma appearing in AIDS; postmenopausal osteoporosity; diabetes; sepsis; arteriosclerosis; and inflammatory diseases (e.g. angitis and hepatitis).
Listed below are literatures relating to the diseases for which the present agent for inhibition of cytokine production or for inhibition of cell adhesion is efficacious.
(1) Literatures relating to transplantation
(a) Kojima, Y. et al., (1993) Cardiovasc. Surg., 1, 577-582
(b) Yamataka, T. et al., (1993) J. Pediatr. Surg., 28, 1451-1457
(c) Stepkowshi, S. M. et al., (1994) J. Immunol., 153, 5336-5346
(2) Literatures relating to asthma
(a) Ohkawara, Y. et al., (1995) Am. J. Respir. Cell Mol. Biol., 12, 4-12
(b) Chihara, J. et al., (1995) Immunol. Lett., 46, 241-244
(c) Hakansson, L. et al., (1995) J. Allergy Clin. Immunol., 96, 941-950
(3) Literatures relating to arterioscrelosis
(a) Poston, R. N. et al., (1992) Am. J. Pathol., 140, 665-673
(b) Ross, P., (1993) Nature, 362, 801-809
(c) Li, H. et al., (1993) Arterioscler. and Thromb., 13, 197-204
(d) Walpola, P. L. et al., (1995) Arterioscler. Thromb. Vasc. Biol., 15, 2-10
(4) Literatures relating to metastasis of cancer
(a) Garofalo, A. et al., (1995) Cancer Res., 55, 414-419
(b) Gardner, M. J. et al., (1995) Cancer Lett., 91, 229-234
(5) Literatures relating to diabetes
(a) McLeod, D. S. et al., (1995) Am. J. Pathol., 147, 642-653
(b) Schmidt, A. M. et al., (1995) J. Clin. Invest., 96, 1395-1403
(c) Jakubowski, A. et al., (1995) J. Immunol., 155, 938-946
(6) Literatures relating to multiple screlosis
(a) Dore-Duffy, P. et al., (1993) Adv. Exp. Med. Biol., 331, 243-248
(b) Mizobuchi, M. and Iwasaki, Y., (1994) Nippon Rinsho, 52, 2830-2836
(c) Cannella, B. and Raine, C. S., (1995) Ann. Neurol., 37, 424-435
(7) Literatures relating to multiple organ failure
(a) Law, M. M. et al., (1994) J. Trauma., 37, 100-109
(b) Anderson, J. A. et al., (1996) J. Clin. Invest., 97, 1952-1959
(8) Literatures relating to atopic dermatitis
(a) Meng, H. et al., (1995) J. Cell Physiol., 165, 40-53
(b) Santamaria, L. F. et al., (1995) Int. Arch. Allergy Immunol., 107, 359-362
(c) Wakita, H. et al., (1994) J. Cutan. Pathol., 21, 33-39
(9) Literatures relating to psoriasis
(a) Groves, R. W. et al., (1993) J. Am. Acad. Dermatol., 29, 67-72
(b) Uyemura K., (1993) J. Invest. Dermatol., 101, 701-705
(c) Lee, M. L. et al., (1994) Australas J. Dermatol., 35, 65-70
(d) Wakita, H. and Takigawa, M., (1994) Arch. Dermatol., 130, 457-463
(10) Literatures relating to chronic rheumatoid arthritis
(a) Hale, P. L. et al., (1993) Arthritis Rheum., 32, 22-30
(b) Iigo Y. et al., (1991) J. Immunol., 147, 4167-4171
(11) Literatures relating to acute respiratory distress syndrome
(a) Tate, R. M. and Repine, J. E., (1983) Am. Rev. Respir. Dis., 128, 552-559
(b) Beutler, B., Milsark, I. W. and Cerami, A. C., (1985) Science, 229, 869-871
(c) Holman, R. G. and Maier, R. V., (1988) Arch. Surg., 123, 1491-1495
(d) Windsor, A. et al., (1993) J. Clin. Invest., 91, 1459-1468
(e) van der Poll, T. and Lowry, S. F., (1995) Prog. Surg. Basel. Karger, 20, 18-32
(12) Literatures relating to ischemic reperfusion injury
(a) Yamazaki, T. et al., (1993) Am. J. Pathol., 143, 410-418
(b) Vaage, J. and Valen, G., (1993) Acand. J. Thorac. Cardiovasc. Surg. Suppl., 41
(c) McMillen, M. A. et al., (1993) Am. J. Surg., 166, 557-562
(d) Bevilacqua, M. P. et al., (1994) Annu. Rev. Med., 45, 361-378
(e) Panes, J. and Granger, D. N., (1994) Dig. Dis., 12, 232-241
(13) Literatures relating to inflammatory bowel disease
(a) Mahida, Y. R. et al., (1989) Gut, 30, 835-838
(b) Nakamura, S. et al., (1993) Lab. Invest., 69, 77-85
(c) Beil, W. J. et al., (1995) J. Leukocyte Bio., 58, 284-298
(d) Jones, S. C. et al., (1995) Gut, 36, 724-730
(14) Literatures relating to systemic inflammatory response syndrome
(a) K. Mori and M. Ogawa, (1996) Molecular Medicine, 33, 9, 1080-1088
(b) Dinarello, C. A. et al., (1993) JAMA, 269, 1829
Specific examples of each of the groups used in the general formula (1) are as follows.
The phenyl group which may have a lower alkoxy group(s) as a substituent(s) on the phenyl ring, include phenyl groups which may have 1-3 straight chain or branched chain alkoxy groups of 1-6 carbon atoms as a substituent(s) on the phenyl ring, such as phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 4-isopropoxyphenyl, 4-pentyloxyphenyl, 4-hexyloxyphenyl, 3,4-dimethoxyphenyl, 3-ethoxy-4-methoxyphenyl, 2,3-dimethoxyphenyl, 3,4-diethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3-propoxy-4-methoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dipentyloxyphenyl, 3,4,5-trimethoxyphenyl, 3-methoxy-4-ethoxyphenyl and the like.
The lower alkyl group includes straight chain or branched chain alkyl groups of 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.
The lower alkoxy group includes straight chain or branched chain alkoxy groups of 1-6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
The lower alkenyl group includes straight chain or branched chain alkenyl groups of 2-6 carbon atoms, such as vinyl, allyl, 2-butenyl, 3-butenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl and the like.
The group represented by xe2x80x94(A)lxe2x80x94NR4R5 (A is a lower alkylene group; R4 and R5, which may be the same or different, are each a hydrogen atom or a lower alkyl group; and l is 0 or 1) includes groups represented by xe2x80x94(A)lxe2x80x94NR4R5 (A is an alkylene group of 1-6 carbon atoms; R4 and R5, which may be the same or different, are each a hydrogen atom or a straight chain or branched chain alkyl group of 1-6 carbon atoms; and l is 0 or 1), such as amino, methylamino, ethylamino, propylamino, isopropylamino, tert-butylamino, butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, methylpropylamino, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl, 6-aminohexyl, 1,1-dimethyl-2-aminoethyl, 2-methyl-3-aminopropyl, methylaminomethyl, ethylaminomethyl, propylaminomethyl, butylaminomethyl, pentylaminomethyl, hexylaminomethyl, dimethylaminomethyl, 2-dimethylaminoethyl and the like.
The hydroxyl group-substituted lower alkyl group includes straight chain or branched chain alkyl groups of 1-6 carbon atoms having 1-3 hydroxyl groups, such as hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5,5,4-trihydroxypentyl, 5-hydroxypentyl, 6-hydroxyhexyl, 1-hydroxyisopropyl, 2-methyl-3-hydroxypropyl and the like.
The lower alkoxy group-substituted lower alkoxy group includes alkoxyalkoxy groups whose alkoxy moities are each a straight chain or branched chain alkoxy group of 1-6 carbon atoms, such as methoxymethoxy, 3-methoxypropoxy, ethoxymethoxy, 4-ethoxybutoxy, 6-propoxyhexyloxy, 5-isopropoxypentyloxy, 1,1-dimethyl-2-butoxyethoxy, 2-methyl-3-tert-butoxypropoxy, 2-pentyloxyethoxy, hexyloxymethoxy and the like.
The lower alkoxycarbonyl group can be exemplified by straight chain or branched chain alkoxycarbonyl groups of 1-6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
The lower alkoxy group-substituted lower alkoxycarbonyl group includes alkoxy group-substituted alkoxycarbonyl groups whose alkoxy moities are each a straight chain or branched chain alkoxy group of 1-6 carbon atoms, such as methoxymethoxycarbonyl, 3-methoxypropoxycarbonyl, ethoxymethoxycarbonyl, 4-ethoxybutoxycarbonyl, 6-propoxyhexyloxycarbonyl, 5-isopropoxypentyloxycarbonyl, 1,1-dimethyl-2-butoxyethoxycarbonyl, 2-methyl-3-tert-butoxypropoxycarbonyl, 2-pentyloxyethoxycarbonyl, hexyloxymethoxycarbonyl and the like.
The carboxyl group-substituted lower alkoxy group includes carboxyl group-substituted alkoxy groups whose alkoxy moiety is a straight chain or branched chain alkoxy group of 1-6 carbon atoms, such as carboxymethoxy, 2-carboxyethoxy, 1-carboxyethoxy, 3-carboxypropoxy, 4-carboxybutoxy, 5-carboxypentyloxy, 6-carboxyhexyloxy, 1,1-dimethyl-2-carboxyethoxy, 2-methyl-3-carboxypropoxy and the like.
The heterocyclic ring residue having 1-2 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom includes, for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholino, pyridyl, 1,2,5,6-tetrahydropyridyl, thienyl, quinolyl, 1,4-dihydroquinolyl, benzothiazolyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrrolyl, carbostyril, 3,4-dihydrocarbostyril, 1,2,3,4-tetrahydroquinolyl, indolyl, isoindolyl, indolinyl, benzimidazolyl, benzoxazolyl, imidazolidinyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, phthaladinyl, carbazolyl, acridinyl, chromanyl, isoindolinyl, isochromanyl, pyrazolyl, imidazolyl, pyrazolidinyl, phenothiazinyl, benzofuryl, 2,3-dihydro[b]furyl, benzothienyl, phenoxathienyl, phenoxazinyl, 4H-chromenyl, 1H-indazolyl, phenazinyl, xanthenyl, thianthrenyl, 2-imidazolinyl, 2-pyrrolinyl, furyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, pyranyl, 2-pyrazolinyl, quinuclidinyl, 1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 3,4-dihydro-2H-1,4-benzthiazinyl, 1,4-benzthiazinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3-dithia-2,4-dihydronaphthalenyl, phenanthridinyl and 1,4-dithianaphthalenyl.
The heterocyclic ring residue having 1-2 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, which has 1-3 groups selected from the group consisting of carboxyl group and lower alkoxy groups, include, for example, 4-carboxy-2-furyl, 5-carboxy-2-furyl, 4-carboxy-2-pyridyl, 6-carboxy-2-pyridyl, 4-methoxy-5-carboxy-2-thiophenyl, 4-carboxy-2-thiazolyl, 2-carboxy-4-pyridyl and 4-carboxy-2-pyrimidyl.
Of the thiazole derivatives represented by the general formula (1), those compounds having basic group react easily with pharmacologically acceptable ordinary acids to form respective salts. Such acids can be exemplified by inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, phosphoric acid, hydrobromic acid and the like; and organic acids such as acetic acid, p-toluenesulfonic acid, ethanesulfonic acid, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, succinic acid, benzoic acid and the like.
Of the thiazole derivatives represented by the general formula (1), those compounds having acidic group react easily with pharmacologically acceptable ordinary basic compounds to form respective salts. Such basic compounds include, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and potassium hydrogencarbonate.
Needless to say, the compounds of the present invention include optical isomers.
Each of the compounds of the general formula (1) is used generally in the form of ordinary pharmaceutical preparation. The pharmaceutical preparation is prepared by using diluents or excipients ordinarily used, such as filler, bulking agent, binder, humectant, disintegrator, surfactant, lubricant and the like. The pharmaceutical preparation can be prepared in various forms depending upon the purpose of remedy, and the typical forms include tablets, pills, a powder, a solution, a suspension, an emulsion, granules, capsules, suppositories, an injection (e.g. solution or suspension), etc. In preparing tablets, there can be used various carriers known in the art. The carriers can be exemplified by excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrators such as dry starch, sodium alginate, powdered agar, powdered laminarin, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan-fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oil and the like; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate and the like; humectants such as glycerine, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; and lubricants such as refined talc, stearic acid salts, boric acid powder, polyethylene glycol and the like. The tablets can be prepared, as necessary, in the form of ordinary coated tablets, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets or film-coated tablets, or in the form of double-layered tablets or multi-layered tablets. In preparing pills, there can be used various carriers known in the art. The carriers can be exemplified by excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oils, kaolin, talc and the like; binders such as powdered acacia, powdered tragacanth, gelatin, ethanol and the like; and disintegrators such as laminarin, agar and the like. In preparing suppositories, there can be used various carriers known in the art. The carriers can be exemplified by a polyethylene glycol, cacao butter, a higher alcohol, a higher alcohol ester, gelatin and a semi-synthetic glyceride. Capsules can be prepared ordinarily by mixing the above-mentioned active ingredient with various carriers mentioned above and filling the resulting mixture into hard gelatin capsules, soft capsules or the like, according to an ordinary method. In preparing an injection (solution, emulsion or suspension), it is sterilized and is preferably made isotonic to the blood. In preparing the solution, emulsion or suspension, there can be used all diluents ordinarily used in the art, such as water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxy-isostearyl alcohol and polyoxyethylene sorbitan-fatty acid esters. In this case, the injection may contain sodium chloride, glucose or glycerine in an amount sufficient to make the injection isotonic, and may further contain a solubilizing adjuvant, a buffer solution, a soothing agent, etc. all ordinarily used. The pharmaceutical preparation may furthermore contain, as necessary, a coloring agent, a preservative, a perfume, a flavoring agent, a sweetening agent and other drugs.
The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly restricted and can be appropriately selected from a wide range, but the desirable amount is generally about 1-70% by weight in the pharmaceutical preparation.
The method for administering the pharmaceutical preparation of the present invention is not particularly restricted. The method is decided depending upon the form of preparation, the age, sex and other conditions of patient, the disease condition of patient, etc. For example, tablets, pills, a solution, a suspension, an emulsion, granules or capsules are administered orally. An injection is intravenously administered singly or in admixture with an ordinary auxiliary solution of glucose, amino acids or the like, or, as necessary, is singly administered intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered intrarectally.
The dose of the pharmaceutical preparation of the present invention is appropriately selected depending upon the administration method, the age, sex and other conditions of patient, the disease condition of patient, etc., but the desirable dose is generally about 0.2-200 mg per kg of body weight per day in terms of the amount of the active ingredient, i.e. the compound of general formula (1) or the salt thereof.